Abstract As of 2014, there are approximately 14.5 million cancer survivors within the United States and this population is projected to grow to 19 million by 2024. Cancer survivors exhibit an accelerated aging phenotype that is hypothesized to be a result of their exposure to chemotherapy. Despite the preponderance of evidence suggesting that this accelerated aging phenotype happens, there are few basic science initiatives poised to study the underlying molecular mechanisms and their therapeutic implications. Cancer survivors have increased bone marrow adiposity, central obesity, serum leptin and triglyceride concentrations, which depict a clinical picture of metabolic dysfunction. These clinical observations suggest that chemotherapy disturbs typical adipose biology. Little is understood about how chemotherapy and DNA-damaging agents can alter the aging of adipose tissue. Adipocytes are post-mitotic and adipogenesis depends on mesenchymal stem cells (MSCs) in these tissues. In addition, most DNA damaging agents damage mitochondrial DNA (mtDNA) more than nuclear DNA, owing to poor mtDNA damage repair. For these reasons, we propose chemotherapy affects MSC mitochondria, allowing for a persistent insult to mitochondrial function after chemotherapy exposure. Mitochondrial health is able to modulate adipogenesis, which may allow damaged mitochondria to drive adipogenesis in MSCs, explaining the clinical phenotype of metabolic dysfunction in cancer survivors. Doxorubicin (DOX), a commonly used DNA damaging agent, has well documented effects on the mitochondria of the heart. These effects on the heart can be summarized as a mitochondrial bioenergetics failure, marked by increased reactive oxygen species (ROS) production, decreased mitochondrial number, and impaired ATP production. Further, metformin (MET) has been found to ameliorate the severity of DOX-induced cardiac injury in various experimental models. Therefore, we hypothesize that DOX treatment of MSCs induces mitochondrial dysfunction that accelerates age-related adipogenesis, which may be ameliorated by metformin. To test these concepts, we will use a series of in vitro and ex vivo approaches to study the aging of MSCs and how DOX contributes to abnormalities in MSC aging, as well as in vivo approaches to study adipose distribution and adipocyte hypertrophy and hyperplasia in our pediatric mouse model of DOX exposure. We will also examine MET's ability to rescue this phenotype Our specific aims are (1) to demonstrate whether DOX treatment induces mitochondrial damage in MSCs, which accelerates adipogenesis in vitro and ex vivo, (2) to define the in vitro and ex vivo roles of MET on MSC adipogenesis following DOX exposure, and (3) to establish the effects of DOX and MET treatment on bone marrow adiposity, lipodystrophy, serum leptin, and serum triglycerides. Upon completion, this study may identify MSCs as a mediator of chemotherapy's effects on adipogenesis, demonstrate the mitochondrial effect of chemotherapy on somatic cells, and identify MET as an FDA approved therapeutic in the treatment of late side effects of chemotherapy.